Hereditary hemochromatosis (HH) is a common genetic disorder characterized by excess iron deposition in the major organs of the body (Dadone et al., 1982, AM. J. Clin. Pathol. 78:196-207; Edwards et al., 1988, N. Engl. J. Med. 18:1355-1362; McLaren, et al., 1995, Blood 86:2021-2027; Bothwell et al., 1995, The metabolic and molecular basis of inherited disease (ed. C. R. Scriver, E. A.) 2237-2269, McGraw-Hill, New York; Bacon et al., 1996, Hepatology, A textbook of liver disease (eds. Zakim, D. & Boyer, T. D.) 1439-1472, W. B. Saunders, Philadelphia). A candidate gene linked to this disease, HFE, was identified by positional cloning (Feder et al., 1996, Nature Genetics 13:399-408). The gene, a novel member of the major histocompatibility complex (MHC) class I family, was found to have a mutation, cysteine 282→tyrosine (C282Y), in 83% of patient chromosomes (Feder et al., 1996, Nature Genetics 13:399-408). This mutation eliminates the ability of HFE to associate with β2-microglobulin (β2 m) and prevents its expression on the cell surface (Feder, et al., 1997, J. Biol. Chem. 272:14025-14028).
Recently, the HFE protein was found to bind the transferrin receptor (TfR) at high affinity, and such binding, in turn, lowers TfR affinity for transferrin, the major iron-binding protein found in the serum (Feder et al., 1998, Proc. Natl. Acad. Sci. U.S.A. 95:1472-1477; Gross et al., 1998, J. Biol. Chem. 273:22068-22074). It has been shown that by lowering the TfR affinity for transferrin, the actual amount of iron taken up by the cell is decreased, as reflected by the disappearance of the cellular iron storage protein, ferritin. These observations suggest that HFE may be important in controlling iron homeostasis by interacting with the TfR.
A murine MHC class I molecule has been shown to interact with the insulin receptor on the cell surface. In addition, a 25 amino acid peptide derived from the alpha-1 domain (residues 61-85) of the murine MHC class I molecule H-2Dk altered the function of the insulin receptor (Stagsted et al., 1990, Cell 62:297-307) by increasing rat adipocyte glucose uptake. This peptide was believed to act as a competitive inhibitor of intact MHC molecules on the cell surface. Additional studies have shown that by inhibiting insulin receptor internalization, the peptide activated a signal-transducing protein on the cell surface which led to increased glucose metabolism. A shortened version of the peptide containing 17 amino acids (residues 69-85) also exhibited similar activities (Stagsted et al., 1993, Proc. Natl. Acad. Sci. U.S.A. 90: 7686-7690). However, prior to the present invention, it was not known if a peptide derived from the HFE protein would mediate a biologic effect on the TfR.